bims-aucach 2022-01-02 papers

Issue of 2022‒01‒02
seven papers selected by
Kleiton Silva
Rowan University

J Biol Chem. 2021 Dec 24. pii: S0021-9258(21)01350-8. [Epub ahead of print] 101540

p53 regulates skeletal muscle mitophagy and mitochondrial quality control following denervation-induced muscle disuse.

Jonathan M Memme, Ashley N Oliveira, David A Hood.

Persistent inactivity promotes skeletal muscle atrophy, marked by mitochondrial aberrations that affect strength, mobility, and metabolic health leading to the advancement of disease. Mitochondrial quality control (MQC) pathways include biogenesis (synthesis), mitophagy/lysosomal turnover, and the mitochondrial unfolded protein response (UPRmt) which serve to maintain an optimal organelle network. Tumor suppressor p53 has been implicated in regulating muscle mitochondria in response to cellular stress; however, its role in the context of muscle disuse has yet to be explored, and whether p53 is necessary for MQC remains unclear. To address this, we subjected p53 muscle-specific knockout (mKO) and wild-type (WT) mice to unilateral denervation. Transcriptomic and pathway analyses revealed dysregulation of pathways pertaining to mitochondrial function, and especially turnover, in mKO muscle following denervation. Protein and mRNA data of the MQC pathways indicated activation of the UPRmt and mitophagy-lysosome systems along with reductions in mitochondrial biogenesis and content in WT and mKO tissue following chronic denervation. However, p53 ablation also attenuated the expression of autophagy/mitophagy machinery, reduced autophagic flux, and enhanced lysosomal dysfunction. While similar reductions in mitochondrial biogenesis and content were observed between genotypes, MQC dysregulation exacerbated mitochondrial dysfunction in mKO fibers, evidenced by elevated reactive oxygen species (ROS). Moreover, acute experiments indicate that p53 mediates the expression of transcriptional regulators of MQC pathways as early as 1 day following denervation. Together, our data illustrate exacerbated mitochondrial dysregulation with denervation stress in p53 mKO tissue, thus indicating that p53 contributes to organellar maintenance via regulation of MQC pathways during muscle atrophy.

Keywords: lysosome; mitochondria; mitochondrial biogenesis; mitochondrial quality control; mitophagy; muscle atrophy; p53; skeletal muscle; transcriptomics; unfolded protein response (UPR)

DOI: https://doi.org/10.1016/j.jbc.2021.101540

Curr Opin Clin Nutr Metab Care. 2021 Dec 28.

Psychological symptoms of illness and emotional distress in advanced cancer cachexia.

Koji Amano, Jane Hopkinson, Vickie Baracos.

PURPOSE OF REVIEW: Cachexia induces both physical and psychological symptoms of illness in patients with advanced cancer and may generate emotional distress in patients and families. However, physical symptoms of cachexia received the most emphasis. The aims of this review are to elucidate a link between systemic inflammation underlying cachexia and psychological symptoms and emotional distress, and to advance care strategy for management of psychological symptoms and emotional distress in patients and families.RECENT FINDINGS: The main themes in the literature covered by this review are psychological symptoms in patients and emotional distress in patients and families. Studies of the underlying biology of cachexia identify the role of the central nervous system to amplify tumor-induced systemic inflammation. The brain mediates a cluster of symptoms, such as sleep disruption, anxiety, cognitive impairment, and reduction in motivated behavior (notably anorexia). These are distressing to patients as well as to families.
SUMMARY: There is growing recognition that holistic multimodal interventions are needed to alleviate psychological symptoms and emotional distress and to improve quality of life in patients with cancer cachexia and families. This is an approach that addresses not only physical health but also psychological, emotional, and social well being issues.

DOI: https://doi.org/10.1097/MCO.0000000000000815

Anticancer Res. 2022 Jan;42(1): 397-405

Moderate Intensity Endurance and Resistance Exercise Attenuates Cachexia in Tumor-bearing Mice.

Nicole R Wood, Jacob Garritson, Alissa Mathias, James M Haughian, Reid Hayward.

BACKGROUND/AIM: Cancer cachexia encompasses several deleterious physiological alterations associated with functional impairments, poor quality of life, and increased mortality. The aim of this study was to examine the effects of chronic moderate intensity exercise training on markers of cachexia.MATERIALS AND METHODS: Balb/c mice were randomly assigned to sedentary (SED) or exercise (EX) groups and EX mice were further randomly assigned to one of three exercise modalities (aerobic, resistance, combined).
RESULTS: Cachexia was induced in SED animals inoculated with C26 cells, as evidenced by significant changes in numerous markers. All cachexia-related perturbations were significantly attenuated in EX versus SED animals. Systemic inflammation was significantly decreased in all EX groups, as evident by a normalization of spleen mass and plasma IL-6.
CONCLUSION: Multiple moderate intensity exercise modalities can provide significant benefits in cachectic mice, and this may be due, at least in part, to decreased systemic inflammation.

Keywords: Cachexia; aerobic exercise; colon cancer; colon-26; inflammation; muscle fiber type; resistance exercise

DOI: https://doi.org/10.21873/anticanres.15498

Mol Neurobiol. 2021 Dec 28.

Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora.

Pasquale Pellegrini, Arnau Hervera, Olga Varea, M Kathryn Brewer, Iliana López-Soldado, Anna Guitart, Mònica Aguilera, Neus Prats, José Antonio Del Río, Joan J Guinovart, Jordi Duran.

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates-the so-called Lafora Bodies (LBs)-in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

Keywords: Epilepsy; Glycogen; Lafora bodies; Lafora disease; Malin; Neuroinflammation; p62

DOI: https://doi.org/10.1007/s12035-021-02682-6

Am J Physiol Cell Physiol. 2021 12 29.

Mitochondrial Quality Surveillance: Mitophagy in cardiovascular health and disease.

Rachel Y Diao, Asa B Gustafsson.

Selective autophagy of the mitochondria, known as mitophagy, is a major mitochondrial quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining the fitness of the mitochondrial population by continuous turnover of aged and less functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents ROS-mediated damaged to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.

Keywords: Parkin; autophagy; heart; mitochondria; mitophagy

DOI: https://doi.org/10.1152/ajpcell.00360.2021

Methods Mol Biol. 2022 ;2445 227-239

Induction and Detection of Mitophagy.

Maria A Yapryntseva, Boris Zhivotovsky, Vladimir Gogvadze.

Mitophagy, a process of selective elimination of mitochondria by autophagy, is a mechanism of mitochondrial quality control that maintains mitochondrial network functionality. The elimination of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Mitophagy impairment is linked to various pathologies; thus, removal of malfunctioning or even harmful mitochondria is vital to cellular physiology. Here, we describe methods that can be applied to the investigation of mitophagy.

Keywords: Autophagy; Confocal microscopy; Flow cytometry; Mitochondria; Mitophagy; Respiration

DOI: https://doi.org/10.1007/978-1-0716-2071-7_14

Methods Mol Biol. 2022 ;2445 3-24

A Balance Between Autophagy and Other Cell Death Modalities in Cancer.

Anna S Gorbunova, Gelina S Kopeina, Boris Zhivotovsky.

Autophagy is an intracellular self-digestive process involved in catabolic degradation of damaged proteins, and organelles, and the elimination of cellular pathogens. Initially, autophagy was considered as a prosurvival mechanism, but the following insights shed light on its prodeath function. Nowadays, autophagy is established as a crucial player in the development of various diseases through interaction with other molecular pathways within a cell. Additionally, disturbance in autophagy is one of the main pathological alterations that lead to resistance of cancer cells to treatment. These autophagy-related pathologies gave rise to the development of new therapeutic drugs. Here, we summarize the current knowledge on the autophagic role in disease pathogenesis, particularly in cancer, and the interplay between autophagy and other cell death modalities in order to combat cancer.

Keywords: Apoptosis; Autophagy; Autophagy-dependent cell death; Cancer; Necroptosis

DOI: https://doi.org/10.1007/978-1-0716-2071-7_1